{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T12:27:04Z","timestamp":1764937624443,"version":"3.41.2"},"reference-count":96,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100006537","name":"Vanderbilt University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006537","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The lipid storage disease Niemann Pick type C (NPC) causes neurodegeneration owing primarily to loss of NPC1. Here, we employed a Drosophila model to test links between glycosphingolipids, neurotransmission and neurodegeneration. We found that Npc1a nulls had elevated neurotransmission at the glutamatergic neuromuscular junction (NMJ), which was phenocopied in brainiac (brn) mutants, impairing mannosyl glucosylceramide (MacCer) glycosylation. Npc1a; brn double mutants had the same elevated synaptic transmission, suggesting that Npc1a and brn function within the same pathway. Glucosylceramide (GlcCer) synthase inhibition with miglustat prevented elevated neurotransmission in Npc1a and brn mutants, further suggesting epistasis. Synaptic MacCer did not accumulate in the NPC model, but GlcCer levels were increased, suggesting that GlcCer is responsible for the elevated synaptic transmission. Null Npc1a mutants had heightened neurodegeneration, but no significant motor neuron or glial cell death, indicating that dying cells are interneurons and that elevated neurotransmission precedes neurodegeneration. Glycosphingolipid synthesis mutants also had greatly heightened neurodegeneration, with similar neurodegeneration in Npc1a; brn double mutants, again suggesting that Npc1a and brn function in the same pathway. These findings indicate causal links between glycosphingolipid-dependent neurotransmission and neurodegeneration in this NPC disease model.<\/jats:p>","DOI":"10.1242\/dmm.050206","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:54:23Z","timestamp":1696946063000},"source":"Crossref","is-referenced-by-count":3,"title":["Glycosphingolipids are linked to elevated neurotransmission and neurodegeneration in a <i>Drosophila<\/i> model of Niemann Pick type C"],"prefix":"10.1242","volume":"16","author":[{"given":"Anna E.","family":"Eberwein","sequence":"first","affiliation":[{"name":"Vanderbilt University and Medical Center 1 Department of Biological Sciences , , Nashville, TN 37235 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swarat S.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Vanderbilt University and Medical Center 1 Department of Biological Sciences , , Nashville, TN 37235 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Rushton","sequence":"additional","affiliation":[{"name":"Vanderbilt University and Medical Center 1 Department of Biological Sciences , , Nashville, TN 37235 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3783-6023","authenticated-orcid":false,"given":"Kendal","family":"Broadie","sequence":"additional","affiliation":[{"name":"Vanderbilt University and Medical Center 1 Department of Biological Sciences , , Nashville, TN 37235 , USA"},{"name":"Vanderbilt University and Medical Center 2 Department of Cell and Developmental Biology , , Nashville, TN 37235 , USA"},{"name":"Vanderbilt Brain Institute, Vanderbilt University and Medical Center 3 , Nashville, TN 37235 , USA"},{"name":"Kennedy Center for Research on Human Development, Vanderbilt University and Medical Center 4 , Nashville, TN 37235 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2023,10,12]]},"reference":[{"key":"2023101209143770100_DMM050206C1","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13024-020-00408-1","article-title":"Glycosphingolipids and neuroinflammation in Parkinson's disease","volume":"15","author":"Belarbi","year":"2020","journal-title":"Mol. 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